1. Field of the Invention
The invention relates generally to genes differentially expressed in animals and particularly to genes differentially expressed in animals administered, on a regular long-term basis, fatty acid amides that affect one or more of food intake, satiety, lipid metabolism, and fat utilization, and to the use of the differentially expressed genes to identify new compounds that affect one or more of those parameters, and to modulate the associated phenotype in an animal.
2. Description of the Related Art
Excess fat and obesity are recognized as a worldwide health problem among humans. The World Health Organization estimates that there are over 1 billion overweight adults, with just under one third of them classified as obese. In addition, obesity is also increasingly recognized as a problem for animals and particularly for companion animals such as dogs and cats. According to the Centers for Disease Control (CDC), obesity is closely associated with at least a risk of other health problems, including hypertension, dyslipidemia, Type II diabetes, heart disease, stroke, sleep apnea, and certain cancers such as breast, endometrial, and colon cancers. Risk factors for an individual becoming obese include genetics, emotions/stress, overeating and a sedentary lifestyle.
The fight against obesity began at least two decades ago with increased public communication on risks linked to excessive obesity. Nutrition recommendations have been established and re-established, widely communicated and even taught in schools. Nevertheless, the number of obese and overweight people is still increasing. In addition to healthy diet and more frequent physical activity, medicines for weight loss are now often prescribed. These medicines function on a variety of levels, including mimicking gastric fullness, reducing appetite, or limiting fat absorption. However, such drugs have not been found satisfactory for long-term treatment, due in part to decreasing effectiveness over time, as well as undesirable side effects. For at least those reasons, patient compliance with anti-obesity medications can be less than satisfactory. Clearly, there is a need in the art to discover and develop new medications or dietary supplements in the fight against obesity.
Fatty acid amides (FAEs) or N-acyl-ethanolamides are structurally related lipids that contain a fatty acid moiety linked to ethanolamine. FAEs are a family of naturally occurring lipids, found in plant and animal tissues, displaying effects on health such as the regulation of energy balance, the control of food intake and also anti-inflammatory properties. FAEs are also formed in-vivo from N-acetylated phosphatidyl-ethanolamide derivatives. The most prevalent FAEs, found in biological tissues such as brain and neuronal cells, are anandamide (N-arachidonoyl-ethanolamine) and N-oleoyl-ethanolamide (OEA). OEA is also found in foodstuffs in low amount, and mainly comes from endogenous synthesis (Di Marzo V, 1999, Life Sci. 65:645-55).
In rodents, intraperitoneal administration of OEA was reported to induce satiety and peripheral utilization of lipid substrate, thereby leading to reduced body fat gain (Thabuis C, et al, 2007, Lipid Technology 19:225-7). Both in-vitro studies and knock-out animal models have revealed some mechanisms of action, such as PPAR-alpha signaling (Fu J, et al, 2003, Nature 425:90-3), FAT/CD36-dependent lipid uptake by the proximal intestine (Yang Y, et al, 2007, Am J Physiol Regul Integr Comp Physiol. 292:R235-41), selected neuron activation (Ahern G P, 2003, J Biol Chem. 278:30429-34), and ghrelin signaling (Cani P D, et al, 2004, Br J. Nutr. 92:757-61). The proximal intestine seems to be a target organ for satiety control (Thabuis C, et al, supra). It has been shown that OEA regulates food intake in wild-type mice but not in PPAR α (−/−) mice. It has been recently shown that OEA can also bind to G-protein coupled cannabinoid receptor GPR119 (Overton H A, et al, 2006, Cell Metab. 3:167-75). When administrated intraperitoneally, OEA reduced food intake by influencing several parameters: decrease of the meal size, delay of the first meal intake and increase of meal intervals (Oveisi F, et al, 2004, Pharmacol Res. 49:461-6). The effects of OEA oral administration has been also examined 24 hours after an acute gavage administration, and has been shown to decrease significantly the food intake over the 12 first hours (Id.). However, the foregoing studies were only performed over short time periods (6 hours to 11 days for intraperitoneal administration, 24 h for oral administration), and long-term effects on satiety or other parameters relating to body fat heretofore have not been shown.
Given the problems with current methods for dealing with obesity, there is a continuing need for new methods and compositions useful for screening substances to determine if they are likely to be useful for promoting a non-obese phenotype in an animal, and using such substances to modulate the amount of adipose tissue on an animal.